tbuckley/cabot-search huggingface dataset:
Predicting outcomes with circulating adrenergic neuroblastoma mRNAs in children with relapsed and refractory neuroblastoma: A BEACON-Neuroblastoma biomarker study.
Authors: Lucas Moreno, Rebekah Weston, Virginie Viprey, Andrei Tchirkov, Maria Corrias, Tim Lammens, Juliet Gray, Cormac Owens, Jennifer Laidler, Marion Gambart, Victoria Castel, Natasha Van Eijkelenburg, Karsten Nysom, Genevieve Laureys, Aurora Castellano, Nicolas U. Gerber, Ruth Lydia Ladenstein, Dominique Valteau Couanet, Keith Wheatley, Susan A Burchill
Journal: Journal of Clinical Oncology (2022)

10039 Background: Children with relapsed and refractory neuroblastoma (RR-NBL) have poor outcomes. Early identification of children at greatest risk of relapse could mean timelier modifications of treatment to improve outcomes. High levels of adrenergic neuroblastoma mRNAs in blood of children with stage M neuroblastoma receiving frontline treatment predict poor outcome (Viprey PMID: 24590653). Since these markers have not been thoroughly studied in the RR-NBL population, we have prospectively evaluated the prognostic potential of the adrenergic neuroblastoma mRNAs paired-like homeobox 2B (PHOX2B ) and tyrosine hydroxylase (TH) in blood from children with RR-NBL treated in the BEACON-Neuroblastoma trial (NCT02308527). Methods: Blood samples collected at baseline from 88 children were analysed by reverse transcriptase polymerase chain reaction (RTqPCR) for PHOX2B and TH mRNAs. The prognostic power of these mRNAs was evaluated using Kaplan-Meier survival curves and Cox proportional hazards regression. Progression-free (PFS) and overall survival (OS) were calculated from the date that the blood sample was taken at screening to the date of an event; progression, disease recurrence, death or censored alive at the last clinical evaluation. Results: Of the children in this cohort, 58 (66%) had relapsed and 30 (34%) had refractory disease. Twenty-three (26%) had MYC-N amplified tumours. TH and PHOX2B mRNAs were detected in 55% and 60% of blood samples respectively; the correlation coefficient between TH and PHOX2B was 0.75. Higher levels of TH, PHOX2B mRNAs or both combined were associated with reduced PFS and OS (Table). For TH, median PFS for children with TH levels below the median was 12 months (95%CI, 4.6–13 months) versus 5.5 months (95%CI, 1.8–9.4 months) for those children with TH levels above the median. For PHOX2B, median PFS for children with PHOX2B levels below the median was 11.5 months (95%CI, 7.6–34 months), compared to 5.7 months (95%CI, 1.8–10.5 months) where levels were above the median. Conclusions: TH and PHOX2B mRNAs in blood collected at baseline identify children with refractory or relapsed neuroblastoma at greatest risk of progression or death. In the RR-NBL setting, this simple blood test could be used to stratify treatment strategies. Clinical trial information: NCT02308527. [Table: see text]
Propensity-matched analysis of concurrent/sequential versus sequential immune checkpoint inhibition in inoperable stage III NSCLC patients treated with chemoradiotherapy.
Authors: Lukas Käsmann, Julian Taugner, Chukwuka Eze, Julian Guggenberger, Saskia Kenndoff, Benedikt Flörsch, Amanda Tufman, Niels Reinmuth, Claus Belka, Farkhad Manapov
Journal: Journal of Clinical Oncology (2022)

e20589 Background: Durvalumab maintenance treatment after completion of concurrent chemoradiotherapy (CRT) in patients with inoperable stage III NSCLC is the international standard. In this propensity-matched analysis, we prospectively evaluated the role of concurrent/sequential versus sequential immune checkpoint inhibition. Methods: Between 10/1/2016 and 12/31/2020, 39 NSCLC patients in stage IIIA/B/C were analyzed. 11 (28%) patients received concurrent/sequential PD-1 inhibition (nivolumab) and 28 (72%) patients received sequential PD-L1 inhibition (durvalumab) up to one year after the end of CRT. A 1:2 propensity score matching (PSM) using age, gender, T category and histology was performed to reduce selection bias and address for confounding factors (n = 33, 11 patients receiving nivolumab (SIM-cohort), 22 patients receiving durvalumab (SEQ-cohort). Treatment-related adverse events were assessed weekly during the CRT and at 6 weeks, 3,6,9, and 12 months after the end of CRT. Results: The median follow-up time of the overall cohort, SIM-I cohort, and SEQ-I cohort was 27.6, 33.3, and 26.5 months after CRT, respectively. For the entire cohort median survival (OS) was not reached; median progression-free survival (PFS) achieved 26.3 months. In the SIM-cohort, median PFS was 22.8 months and median OS was not reached. In the SEQ-cohort, neither median PFS nor OS was reached. PFS at 12/24 months was 82/44% in the SIM-cohort and 57/57% in the SEQ-cohort (p = 0.714), respectively. In the SIM-cohort, 18.2% of patients showed grade III pneumonitis; in the SEQ-cohort 13.6% (p = 0.735). Grade 4 and 5 toxicities were not observed. Conclusions: Both concurrent/sequential and sequential immune checkpoint inhibition shows a favorable side effect profile and promising survival in terated patients. Concurrent immunotherapy did not result in an improved outcome (PFS, OS) compared to sequential approach. However, our propensity-matched analysis found that concurrent immunotherapy was associated with a non-significant moderate increase in grade III pneumonitis.
Racial differences in cardiovascular disease mortality among cancer survivors.
Authors: Hyuna Sung, Noorie Hyun, Rebecca Siegel, Ahmedin Jemal
Journal: Journal of Clinical Oncology (2022)

12075 Background: Cancer survivors have an elevated risk of death from cardiovascular disease (CVD). Whether the risk differs by race/ethnicity and cancer type has not been fully explored in the U.S. Methods: Data from survivors of top 23 cancers diagnosed at ages 20 to 64 years during 2000-2018 were obtained from 17 Surveillance, Epidemiology, and End Results registries. Risks for CVD death among survivors relative to the general population were calculated using standardized mortality ratios (SMRs) in each racial/ethnic group: Non-Hispanic White (NHW), Non-Hispanic Black (NHB), Hispanic, Non-Hispanic Asian or Pacific Islander (API), and Non-Hispanic American Indian (AI). Among survivors, the risks were compared by race/ethnicity using cause-specific proportional hazards models for competing risks, controlling for year of diagnosis, age at diagnosis, sex, stage (when appropriate), and the first course of treatment receipt (surgery, radiotherapy, chemotherapy). Results: Among 2,806,515 survivors (NHW, 68%; NHB, 13%; Hispanic, 12%; API, 7%; AI, 0.5%), 57,883 CVD deaths occurred during 6.4 person-years of mean follow-up (32 per 10,000). Cancer survivors overall were at increased risk of CVD death compared to their general population counterpart with an SMR of 1.76 among API (95% CI = 1.69-1.84; 8.7 excess deaths per 10,000), 1.49 among AI (95% CI = 1.33-1.68; 11.9 excess deaths per 10,000), 1.46 among Hispanic (95% CI = 1.41-1.50; 7.4 excess deaths per 10,000), 1.30 among NHB (95% CI = 1281-1.33; 14.9 excess deaths per 10,000), and 1.13 among NHW (95% CI = 1.12-1.14; 3.4 excess deaths per 10,000) survivors. Compared with NHW survivors, the adjusted hazard of CVD death was statistically significantly higher among NHB survivors for 23/23 cancers and among AI survivors for 9/18 cancers but was statistically significantly lower among Hispanic survivors for 5/23 cancers and among API survivors for 10/23 cancers, with no significant difference otherwise. The highest hazards ratios (HRs) were among NHB survivors of melanoma (HR = 3.19, 95% CI = 2.11-4.83); breast (HR = 2.73, 95% CI = 2.57-2.89); pancreatic (HR = 2.63, 95% CI = 2.19-3.16); and testicular (HR = 2.59, 95% CI = 1.62-4.14) cancers, whereas the lowest HRs were among API survivors of head and neck (HR = 0.53, 95% CI = 0.44-0.63) and cervical (HR = 0.57, 95% CI = 0.41-0.80) cancers and Hispanic survivors of cervical cancer (HR = 0.59, 95% CI = 0.46-0.75). Conclusions: The risk of CVD death differs considerably among cancer survivors by race/ethnicity and cancer types, highlighting the need for targeted prevention and surveillance in primary care. Future studies are needed to identify factors that contribute to this variation in order to inform efforts towards mitigating risk.
Blood based multigene testing using next generation sequencing to guide management in solid tumors: Experience from Augusta-Georgia.
Authors: Nabin Raj Karki, Jigar Parikh, Priyanka Raval, Asha Nayak, Nagla Fawzy Abdel Karim
Journal: Journal of Clinical Oncology (2022)

e15023 Background: The pool of somatic alterations with prognostic and predictive significance in management of solid tumors is rapidly expanding. Multigene panel testing using next generation sequencing (NGS) technology from peripheral blood specimen is convenient and readily available in most oncology practices. Widespread adoption is lagging, in part due to anticipation of low probability of finding an actionable information. We share our experience of real-world utilization of this technology. Methods: Blood based next generation testing ordered by providers in Georgia (outside Atlanta) between January 1, 2015, and December 31, 2021, via Guardant platform for all solid tumors was included in this analysis. Guardant360 and Guardant360CDx assays sequenced circulating cell-free DNA to detect somatic alterations in up to 83 cancer associated genes. Data was obtained from Guardant360 on site of cancer, comprehensive genomic profile, and therapeutic options at the time of report. Results: 25 providers in Georgia from 11 institutions sent 335 blood samples from solid cancer patients. There were 192 males and 143 females. Most common cancers were lung and bronchus (45%), prostate (13%), breast (11%), pancreaticobiliary (8%), colorectal (4%), melanoma (3%) and kidney (3%). Any somatic mutations were detected in 85% (285/335) patients. A total 1524 alterations comprising of 977 unique alterations involving 83 genes were detected, with an average of 5.3 unique genomic alterations per patient. The genes that were altered at least 2% of times were TP53 (20%), ATM (5.5%), PI3KCA (4.3%), KRAS (3.8%), APC (3.5%), AR (2.8%), PDGFRA (2.8%), ARIDIA (2.5%) and BRAF (2.2%). Of all alterations, 11% (170/1524) were synonymous and 31% (474/1524) were variant of unknown significance. 85 samples had tumor mutational burden (TMB) results available, with 55% (47/85) having TMB &gt; 10 mut/Mb. The average TMB was 14.9 mutations/Mb. Out of 252 specimens evaluated for microsatellite instability (MSI), 1 had high MSI. An FDA approved drug targeting the alteration/pathway was available for the same cancer in 4% (77/1524) and for other cancers in 19% (291/1524) of alterations. An approved drug matched to the alteration was available for the same cancer in 16% (54/335) patients and for other cancers in 45% (153/335) patients. 12.5% (42/335) patients were predicted not to benefit from certain drugs. 74% (249/335) had a clinical trial available for the mutations present. Conclusions: Eighty five percent solid tumor patients had a positive result in blood based NGS. Seventy four percent patients had at least one therapeutically applicable (suggestion for a drug to target the alteration approved for the same/different cancers or lack of benefit due to the alteration) information. Thus, blood based NGS yields clinically relevant and actionable information to guide management in solid tumors.
A phase II study of gemcitabine plus cisplatin chemotherapy in patients with muscle-invasive bladder cancer with bladder preservation for those patients whose tumors harbor deleterious DNA damage response (DDR) gene alterations (Alliance A031701).
Authors: Gopa Iyer, Karla V. Ballman, Pamela J. Atherton, Katie Murray, Young Kwok, Preston D. Steen, Shiva Baghaie, Jonathan E. Rosenberg, Michael J. Morris
Journal: Journal of Clinical Oncology (2022)

TPS4615 Background: While a standard approach to muscle-invasive bladder cancer (MIBC) management involves neoadjuvant cisplatin-based chemotherapy (NAC) followed by radical cystectomy (RC), up to 50% of pts recur with metastatic disease. Moreover, removal of the bladder has a significant impact on pts’ quality of life. Pathologic downstaging to non-muscle-invasive disease (&lt;pT2) or complete response (pT0) at RC is associated with long-term survival benefit. Somatic DDR gene alterations were shown to be enriched in pts who were pT0 at RC following NAC in multiple retrospective analyses. We hypothesize that MIBC pts with somatic loss-of-function alterations within specific DDR genes and clinical responses to NAC can be uniquely managed with a bladder-sparing approach consisting of close cystoscopic and radiographic surveillance, avoiding the toxicities of definitive local therapy. Methods: A031701 is a multicenter phase II trial that will enroll 271 pts with T2-T4aN0/xM0 MIBC diagnosed within 60 days prior to enrollment. Multifocal MIBC, tumors &gt;5 cm by cystoscopic assessment, and Bacillus Calmette-Guérin (BCG)-refractory disease (beyond standard induction and maintenance) are not allowed. Intravesical chemotherapy is allowed. Pts must be eligible for cisplatin chemotherapy. Eligible pts will receive either standard dose or dose dense gemcitabine and cisplatin chemotherapy (investigator’s choice) with simultaneous genetic sequencing of pre-treatment transurethral resection specimens. Pts whose tumors contain deleterious alterations in any 1 of 9 pre-selected DDR genes ( ERCC2, ERCC5, BRCA1, BRCA2, RECQL4, RAD51C, ATM, ATR, and FANCC) and who exhibit &lt;T1 response on clinical restaging are eligible for organ-sparing management. Pts without deleterious DDR gene alterations or with &gt;T1 disease after NAC will undergo RC or chemoradiation therapy (investigator/patient choice). The primary endpoint is 3-year event-free survival in DDR-altered pts who undergo bladder sparing, defined as the proportion of pts without BCG-unresponsive non-muscle invasive recurrences, any &gt;T2 recurrences, or any metastatic recurrences. Secondary endpoints include clinical response rate (&lt;cT1) in patients with deleterious DDR gene alterations following NAC, bladder-intact survival, overall survival, pT0 rate in DDR-altered pts who elect to undergo RC, pT0 rate in pts without DDR gene alterations, 3-year RC rate in pts with DDR gene alterations, and proportion of pts undergoing intravesical management for in-bladder recurrences. The study opened for enrollment in September 2018. Support: U10CA180821, U10CA180882. Clinical trial information: NCT03609216.
Hormonal indicator of effective mobilization of antitumor mechanisms in the experiment.
Authors: Galina V. Zhukova, Alla I. Shikhlyarova, Elena M. Frantsiyants, Irina V. Kaplieva, Marina A. Engibaryan, Viktoriya L. Volkova, Yulia V. Ulianova, Pavel V. Chernogorov, Tatiana V. Ausheva, Oleg I. Kit
Journal: Journal of Clinical Oncology (2022)

e15054 Background: Previously, the antitumor efficacy of low intensity complex impacts, including electromagnetic radiation (EMR) of the extremely high frequency range (EHF) in combination with factors of electromagnetic or biochemical nature, was shown. The questions about systemic antitumor mechanisms and the role of the thyroid system in them are opened. The aim of the study was to evaluate changes in the levels of thyroid hormones and their ratio in the blood in the cases of tumor regression under the influence of complex impacts including EMR EHF. Methods: The experiments were carried out on outbred male rats of young (8-9 months) and senile (24-26 months) age with subcutaneously transplanted sarcoma 45 (S-45). EMR EHF (42.2 GHz, 10 mW/cm 2 ) with previously developed regime of modulation was applied on the head. In young males (21), the tumor was additionally exposed to the electric field with neuron-like impulses (SCENAR-97.1 device); in 20 old animals, complexes of essential L-amino acids were used per os 260 mg/kg/day. The impact course lasted for 3 weeks. After its completion, the levels of thyroxine (T4) and triiodothyronine (T3) in the blood were assessed by radioimmunoassay and the T3/T4 ratio was calculated. The results were compared with the values in intact animals (n=9-10), control group rats (S-45, n=11-15) and animals of the main groups without tumor regression. The Kruskal-Wallis and Mann-Whitney criteria were used, and the coefficient of variation (cv) was determined. Results: The tumor growth was accompanied by a decrease in T3 by 1.7-2 times (p &lt;0.05) without changes in T4. The studied impacts caused a complete regression of S-45 in 38% (8) of young males, as well as a regression by 75-100% in 25% (5) of old animals. Young rats with S-45 regression showed no decrease in T3, while in old animals the T3 decrease was 1.3 times less pronounced than in the control group (p &lt;0.05). In young males without S-45 regression, a decrease in T3 at the tendency level was observed (p &lt;0.1), and T3 in old rats did not differ from the control group. The level of T4 did not change. In all cases of S-45 regression, despite the variability of T3 and T4 separately (cv=31-68%), practically constant value of the T3/T4 ratio was noted (cv=2-4%). It was 16x10 -5 in young animals and 13x10 -5 in old ones. It differed by 12-94% from the T3/T4 in the comparison groups and in rats without tumor regression (p &lt;0.05-0.01). In the latter cases, the T3/T4 ratio had significant variability (cv = 25-84%) and was outside the range of values in rats with tumor regression. Conclusions: The results indicate the participation of the thyroid gland in the effective mobilization of systemic antitumor mechanisms, the marker of which is the ratio of the thyroid hormone levels in the blood.
Are we doing it right? Mentorship challenges for oncology fellows and early-career faculty from backgrounds underrepresented in medicine.
Authors: Dame Idossa, Ana I. Velazquez Manana, Miki Horiguchi, Julia Alberth, Inas Abuali, Demetria Joy Smith-Graziani, Gilberto Lopes, Sam Joseph Lubner, Narjust Duma
Journal: Journal of Clinical Oncology (2022)

11047 Background: Physician workforce diversity can be a driver of institutional excellence, improving innovation and reducing health disparities. The current diversity of the hematology/oncology (HO) workforce does not reflect that of the US population. The role of mentorship in increasing HO fellows’ interest in pursuing careers in HO has been described previously. However, the mentorship experiences of fellows and early career faculty from backgrounds underrepresented in medicine (UIM) in HO has not been fully characterized. Therefore, we compared the mentorship experiences of UIM and non-UIM trainees and early career faculty in HO subspecialties. Methods: We conducted cross-sectional online survey of HO subspecialists including current fellows and faculty within 5 years of end of training. The anonymous survey was distributed via email and social media channels in April 2020. Fisher’s exact test and multivariable logistic regression models were used to conduct comparisons between study groups. Results: Of the 306 respondents, 64 (21%) were UIM and 161 (53%) identified as male. UIM participants were less likely to have a primary mentor (66%) than non-UIM participants (80%, p = 0.015). Among those who had a primary mentor, UIMs were more likely to meet infrequently (greater than every 3 months, p = 0.007). Furthermore, UIMs were more likely to report having mentors outside their own institution (47% vs 40% non-UIM, p = 0.002) and making compromises to gain access to mentorship (36% vs 23% non-UIM, p = &lt; 0.001). In addition, UIM participants were less likely to have an advisor (38% vs 54% non-UIM, p = 0.017), a coach (13% vs 20% non-UIM, p = 0.054), or a sponsor (19% vs 26% non-UIM, p = 0.046). UIMs were also less likely to apply for grants (34% vs 42% non-UIM, p = 0.035) and awards (28% vs 43%, non-UIM p = 0.019). In multivariable models, UIM individuals were more likely to make compromises to gain access to mentors (OR = 1.96, p = 0.047) and this remained significant for females (OR = 2.17, p = 0.005). Lastly, US born individuals had higher odds of having a primary mentor than non-US-born individuals (OR = 2.43, p = 0.004). Conclusions: In the largest study to date characterizing the mentorship experience of HO trainees and junior faculty, we found that UIM individuals were significantly less likely to find effective mentorship and were less likely to apply for awards and grant support. Understanding the challenges of UIM trainees can help shape training environments in academic medicine to ensure these are grounded in diversity and inclusion. Given the importance of workforce diversity, training programs in HO must consider structured programs and other innovations to improve mentoring experiences of UIM trainees and junior faculty.
Detection of multiple types of cancer driver mutations using targeted RNA sequencing in NSCLC.
Authors: Yuanyuan Hong, Xiaoqing Wang, Weina Mu, Xuexia Zeng, Lin Su, Xiaojing Lin, Zhuo Zhang, Qi Zhang, Weizhi Chen
Journal: Journal of Clinical Oncology (2022)

e15043 Background: DNA NGS sequencing has been widely used as a companion diagnostic method for matching NSCLC patients with appropriate personalized target therapy. RNA-based NGS has been proved to be valuable in detecting fusion and exon skipping mutations and therefore recommended by NCCN guidelines for these mutation types. It would be helpful to have a diagnostic method that suits different types of clinically actionable mutations in a single tube. Methods: We developed an RNA-based hybridization panel targeting actionable driver oncogenes in solid tumors. Experimental and bioinformatics pipelines were optimized for detection of fusion, SNV and indel mutations, as well as gene expression quantification. Reference materials were used for analytical validation of the panel, and 1253 FFPE samples from NSCLC patients were analyzed by DNA panel sequencing and RNA panel sequencing in parallel to assess the performance of the RNA panel in detection of multiple types of clinically actionable mutations. Results: Analytical validation showed a detection specificity of 100.0% for SNVs and fusions. The targeted RNA panel achieved a 1.45-3.15 copies/ng limit of detection (LOD) for SNVs and a 0.21-6.48 copies/ng LOD for fusions. Gene expression analysis revealed a correlation greater than 0.9 between the RNA-seq and targeted RNA panel results. Among 1253 NSCLC FFPE samples, multiple mutation types were called at both DNA and RNA levels and compared between the two assays. Twenty-one fusion and six METex14 skipping events were only detected by the RNA panel. The positive percent agreement (PPA) and positive prediction value (PPV) were 98.08% and 98.62% for targetable SNVs and 98.15% and 99.38% for targetable Indels, respectively. We also explored the relationship of RNA expression with gene copy number and protein expression. The RPKM (reads per kilobase per million mapped reads) of EGFR transcripts exhibited a linear relationship with copy number, whereas MET gene expression seemed to be regulated in a more complexed manner. In IHC analysis, all MET IHC 3+ samples had significantly higher RPKM levels than samples with MET IHC level of 2+/1+. Conclusions: Parallel DNA and RNA systematic analysis demonstrated the accuracy and robustness of the RNA sequencing panel for detection of multiple types of clinically actionable mutations. The simplified experimental workflow, lowered cost and sample consumption, along with the superior performance in simultaneous detection of multiple types of mutations will make RNA panel sequencing an effective method in clinical testing for NSCLC.